Benzofuran 2-carboxylic acid hydrazides useful as inhibitors of leukotriene biosynthesis

ABSTRACT

Compounds of the Formula I:    &lt;IMAGE&gt;  I  and pharmaceutically acceptable salts thereof are inhibitors of leukotriene biosynthesis. These compounds inhibit the mammalian 5-lipoxygenase enzyme, thus preventing the metabolism of arachidonic acid to the leukotrienes. These compounds are thus useful in the treatment of asthma, allergic disorders, inflammation, skin diseases and certain cardiovascular disorders.

This application is a division of Ser. No. 001,262, filed Jan. 7, 1987, now U.S. Pat. No. 4,745,127, which is a division of Ser. No. 725,265, Apr. 19, 1985, now U.S. Pat. No. 4,663,347, and a continuation-in-part of Ser. No. 800,624, filed Nov. 21, 1985, now abandoned, which is a continuation of Ser. No. 584,061, filed Feb. 27, 1984, now abandoned, and a continution-in-part of Ser. No. 661,645, filed Oct. 17, 1984, now abandoned, which is a continuation-in-part of Ser. No. 547,508, filed Oct. 31, 1983, now abandoned.

This invention is directed to pharmaceutical compositions containing a compound of the Formula I: ##STR2## and pharmaceutically acceptable salts thereof wherein the various substituents are as defined herein below:

Z is a bond, CR₁₄ ═CR₁₅ or CHR₁₄ --CHR₁₅ ;

X is O, S, SO, or SO₂ ;

R₂ is H, OH, C₁ to C₂₀ alkoxy, including straight chain or branched chain, cycloalkyl, bicycloalkyl, tricycloalkyl or tetracycloalkyl; Ar₁ --C₁ to C₃ alkoxy; NR₈ Ar₁, wherein R₈ and Ar₁ can optionally be joined to form a heterocyclic ring having 5 to 8 ring atoms; --NR₈ Het; --N(R₈)CH₂ Ar₁ ; --N(R₁₃)--N(R₁₃)₂ wherein each R₁₃ is independently hydrogen, R₈, R₉, Ar₁ or Het; --NH--CH═C(Ar₁)₂ ; --O(CH₂)_(n) NR₈ R₉ wherein n is 2 to 4; --Z--Ar₁ ; ##STR3## --lower acyloxy-lower alkoxy (e.g. ##STR4## --CH₂ OH; --(CH₂)_(n) Ar₁ wherein n is 0 to 3; --(CH₂)_(n) COOR₆ wherein n is 0 to 6; C₁ to C₂₀ alkyl; Ar₁ ; Het; (CH₂)_(n) NR₈ R₉ wherein n is 1 to 3; or Het; ##STR5## and R₁, R₃, R₄, T and V are each independently selected from:

(1) hydrogen;

(2) alkyl having 1 to 6 carbon atoms;

(3) alkenyl having 2 to 6 carbon atoms;

(4) --(CH₂)_(n) M wherein

n is 0 to 6 except when X is S and M is OR₅, in which case n is 1 to 6 and

M is

(a) --OR₅ ;

(b) halogen;

(c) --CF₃ ;

(d) --SR₅ ;

(e) Ar₁ ;

(f) --COOR₆ ;

(g) ##STR6## wherein R₁₂ is H, C₁ to C₆ alkyl, or Ar₁ ; (h) tetrazole;

(i) ##STR7## (j) ##STR8## (k) ##STR9## (l) ##STR10## (m) --NR₈ R₉ ; (n) --NHSO₂ R₁₀ wherein R₁₀ is OH, C₁ to C₆ alkyl, CF₃, C₁ to C₆ -alkoxy, or Ar₁ ;

(o) ##STR11## (p) --SOR₅ ; (q) --CONR₈ R₉ ;

(r) --SO₂ NR₈ R₉ ;

(s) --SO₂ R₅ ;

(t) --NO₂ ; or

(u) --CN;

or any two of R₃, R₄, T and V may be joined to form a saturated ring having 5 or 6 ring atoms, said ring atoms comprising 0, 1 or 2 atoms selected from oxygen and sulfur, the remaining ring atoms being carbon;

each R₅ is independently H, C₁ to C₆ alkyl, benzyl, Ar₁, perfluoro-C₁ to C₄ alkyl, CH₂ --R₁₁ wherein R₁₁ is C₁ to C₅ alkyldimethylamino, hydroxy-C₂ to C₅ alkyl, CH₂ COOR₆, or CH₂ CO--R₇ ;

each R₆ is independently H or C₁ to C₆ alkyl;

each R₇ is independently C₁ to C₆ alkyl, benzyl, Ar₁, NR₈ R₉, NHAr₁, or O--C₁ to C₄ alkyl;

each R₈ and each R₉ is independently H or C₁ to C₄ alkyl, or R₈ and R₉ may be joined through the N to which they are attached to form a heterocycloalkyl ring having 5 to 8 ring atoms;

each Het is independently an aromatic heterocyclic ring having 5 or 6 ring atoms, one or more of which are selected from N, O and S;

each Ar₁ is independently 1- or 2- naphthyl, phenyl or mono- or disubstituted phenyl, wherein the substituents on the phenyl are independently selected from C₁ to C₃ alkyl, I, Br, Cl, F, COOR₆, (CH₂)_(n) --NR₈ R₉ wherein n is 0 to 2, methylenedioxy, C₁ to C₃ alkoxy, OH, CN, NO₂, CF₃, C₁ to C₄ acyl, NR₈ R₉, S--C₁ to C₆ alkyl, SO--C₁ to C₆ alkyl, and SO₂ --C₁ to C₆ alkyl; and

R₁₄ and R₁₅ are each independently H or C₁ to C₆ alkyl.

This invention also provides a method of treatment for disease states caused by the synthesis of the Leukotrienes C₄, D₄, E₄ and F₄, as well as Leukotriene B₄, in mammals especially in a human subject. This method comprises administering to said subject an effective amount of a compound of Formula I combined with an appropriate pharmaceutical carrier.

The compounds of Formula I may be used to treat or prevent mammalian (especially human) disease states such as erosive gastritis; erosive esophagitis; inflammatory bowel disease; ethanol-induced hemorrhagic erosions; hepatic ischemia; noxius agent induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CCl₄ and D-galactosamine; ischemic renal failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced renal failure.

Finally, this invention also provides novel compounds within the Formula I that act as inhibitors of the mammalian 5-lipoxygenase enzyme system, thus preventing the biosynthesis of the Leukotrienes C₄, D₄ and E₄ and also Leukotriene B₄. U.S. Pat. No. 4,663,347 (Atkinson et al.) is incorporated herein by reference in its entirety. 

What is claimed is:
 1. A compound of the formula: ##STR12## wherein the substituents for a compound are selected from the following groups:

    __________________________________________________________________________     Compound                                                                             X R.sub.1                                                                           R.sub.2            R.sub.3      R.sub.4                             __________________________________________________________________________     116   O CH.sub.3                                                                          NHNHPhp-NO.sub.2   6-OH         H                                   117   O CH.sub.3                                                                          NHNHPh             4-OH         H                                   118   O CH.sub.3                                                                          NHNHPhp-OMe        5-OH         H                                   119   O CH.sub.3                                                                          NHNHPhp-OMe        4-OH         H                                   120   O CH.sub.3                                                                          NHNHPhp-OMe        4-OAc        H                                   121   O CH.sub.3                                                                          NHNHPhp-NO.sub.2   4-OH         H                                   122   O CH.sub.3                                                                          NHNHPhp-NO.sub.2   4-OAc        H                                   123   O CH.sub.3                                                                           ##STR13##         4-OAc        H                                   124   O CH.sub.3                                                                          NHNHPhp-Cl         4-OAc        H                                   125   O CH.sub.3                                                                          NHNHPhp-Cl         6-OH         H                                   126   O CH.sub.3                                                                          NHNHPhp-Cl         4-OH         H                                   127   O CH.sub.3                                                                          NHNHPhp-Cl                                                                                         ##STR14##   H                                   128   O CH.sub.3                                                                          NHNHPhm-OMe        4-OH         H                                   129   O Ph NHNHPhp-OMe        6-OAc        H                                   130   O CH.sub.3                                                                          NHNHPhp-Cl         5,6-OCH.sub.2 O                                                                             H                                   131   O CH.sub.3                                                                          NHNHPhp-Cl         5-OAc        6-OAc                               132   O CH.sub.3                                                                          NHNHPhp-Cl         5-OH         6-OH                                133   O CH.sub.3                                                                          NHNHPh p-OMe                                                                                       ##STR15##   H                                   135   O CH.sub.3                                                                          NHNHPh                                                                                             ##STR16##   H                                   136   O Ph NHNHPhp-OMe        6-OH         H                                   137   O CH.sub.3                                                                          NHNHPh3,4-Cl.sub.2 4-OH         H                                   138   O CH.sub.3                                                                          NMeNMePh           4-OH         H                                   139   O CH.sub.3                                                                          NMeNMePh           4-OAc        H                                   140   O CH.sub.3                                                                          NHNHPh3,4-Cl.sub.2 4-OAc        H                                   141   O CH.sub.3                                                                           ##STR17##         4-OAc        H                                   142   O CH.sub.3                                                                          NHNHPhp-Cl         5-OAc        H                                   143   O CH.sub.3                                                                          NHNHPhp-Cl         5-OH         H                                   144   O CH.sub.3                                                                          NHNHPhm-OMe        4-OAc        H                                   145   O CH.sub.3                                                                          NHNHPh                                                                                             ##STR18##   H                                   146   O CH.sub.3                                                                          NHNHPhp-OMe        4-OH         5-Pr                                147   O CH.sub.3                                                                          NHNHPhp-OMe        4-CH.sub.2 CHCH.sub.2                                                                       5-OAc                               148   O Pr NHNHPhp-OMe                                                                                        ##STR19##   H                                   149   O Pr NHNHPhp-OMe        6-OAc        H                                   150   O Pr NHNHPhp-OMe        6-OH         H                                   151   O CH.sub.3                                                                          NEtNHPh            4-OAc        H                                   152   O CH.sub.3                                                                          NEtNHPh            4-OH         H                                   153   O CH.sub.3                                                                          NHNHPhp-OMe                                                                                        ##STR20##   H                                   154   O CH.sub.3                                                                          NHNHPhp-Cl                                                                                         ##STR21##   H                                   155   O CH.sub.3                                                                          NHNHPhp-OMe                                                                                        ##STR22##   5-CH.sub.2 CHCH.sub.2               156   O CH.sub.3                                                                          NMeNMePh                                                                                           ##STR23##   H                                   157   O CH.sub.3                                                                          NHNHPhp-Cl                                                                                         ##STR24##   H                                   158   O CH.sub.3                                                                          NHNHPhp-OMe                                                                                        ##STR25##   5-Pr                                159   O CH.sub.3                                                                          NHNHPh3,4-Cl.sub.2                                                                                 ##STR26##   H                                   160   O CH.sub.3                                                                          NHNHPhp-Cl                                                                                         ##STR27##   H                                   161   O CH.sub.3                                                                          NHNHPhp-OMe                                                                                        ##STR28##   H                                   269   O CH.sub.3                                                                          NMeNMePhp-F        5-OH         6-OH                                270   O CH.sub.3                                                                          NHNMePhp-F         5-OH         6-OH                                271   O CH.sub.3                                                                          NHNMePhp-Cl        5-OH         6-OH                                272   O CH.sub.3                                                                          NHNMePhp-Cl        5-OH         6-OH                                273   O CH.sub.3                                                                          NHNMePhp-F         4-OH         H                                   274   O CH.sub.3                                                                          NMeNMePhp-F        4-OH         H                                   279   O CH.sub.3                                                                          NHNMePhp-CF.sub.3  4-OH         H                                   285   O CH.sub.3                                                                          NHNMePhp-F         4-OH         5-Pr                                286   O CH.sub.3                                                                          NHNMePHp-F         5-OH         H                                   287   O CH.sub.3                                                                          NHNMePh            4-OH         H                                   __________________________________________________________________________


2. A compound of claim 1 which is: 117-133, 135-161, or
 287. 3. A compound of claim 1 which is: 117, 126, 127, 132, 138, 146, or
 154. 4. A compound of the Formula Ic: ##STR29## wherein R₁ is hydrogen, C₁ to C₆ alkyl, Ar₁ --C₁ to C₃ alkyl, Ar₁ or CH₂ OH;R₃, R₄ and T are each independently selected from:(1) hydrogen; (2) alkyl having 1 to 4 carbon atoms; (3) alkenyl having 2 to 4 carbon atoms; (4) --(CH₂)_(n) M whereinn is 0 or 1, and M is(a) --OR₅ ; (b) halogen; (c) --CF₃ ; (d) --SR₅ ; (e) Ar₁ ; (f) --COOR₆ ; (g) ##STR30## wherein R₁₂ is H, C₁ to C₆ alkyl, or Ar₁ ; (h) ##STR31## (i) ##STR32## (j) ##STR33## (k) ##STR34## (l) NR₈ R₉ ; (m) --NHSO₂ R₁₀ wherein R₁₀ is C₁ to C₆ alkyl, phenyl, p-tolyl or CF₃ ; (n) --SOR₅ ; (o) --CONR₈ R₉ ; (p) --SO₂ NR₈ R₉ ; (q) --SO₂ R₅ ; (r) k--NO₂ ; or (s) --CN; or any two of R₃, R₄ and T may be joined to form a saturated ring having 5 or 6 ring atoms, said ring atoms comprising 0, 1 or 2 oxygen atoms, the remaining ring atoms being carbon; each R₅ is independently H, C₁ to C₆ alkyl, benzyl Ar₁, perfluoro-C₁ -C₄ alkyl, CH₂ --R₁₁ wherein R₁₁ is hydroxy C₂ to C₅ alkyl, CH₂ COOR₆, or CH₂ CO--R₇ ; each R₆ is independently H or C₁ to C₆ alkyl; each R₇ is independently C₁ to C₆ alkyl, benzyl, Ar₁, NR₈ R₉, NHAr₁, O--C₁ to C₄ alkyl; each R₈ and each R₉ is independently H or C₁ to C₄ alkyl, or R₈ and R₉ may be joined through the N to which they are attached to form a heterocycloalkyl ring having 5 to 8 ring atoms; each R₁₃ is independently hydrogen, R₈, R₉, or Ar₁, and each Ar₁ is independently 1- or 2-naphthyl, phenyl or mono- or disubstituted phenyl, wherein the substituents on the phenyl are independently selected from C₁ to C₃ alkyl, I, Br, Cl, F, COOR₆, (CH₂)_(n) --NR₈ R₉ wherein n is 0 to 2, methylenedioxy, C₁ to C₃ alkoxy, OH, CN, NO₂, CF₃, C₁ to C₄ acyl, NR₈ R₉, S--C₁ to C₆ alkyl, SO--C₁ to C₆ alkyl, and SO₂ --C₁ to C₆ alkyl; with the proviso that at least one of the R₁₃ groups in the Formula Ic is Ar₁, and one of R₃, R₄ and T is OR₅ or --OCOR₇ ;or a pharmaceutically acceptable salt thereof.
 5. A method of inhibiting mammalian leukotriene biosynthesis or actin which comprises administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of claim
 1. 6. A method of claim 5 wherein the mammal is a human.
 7. A method of treating pulmonary conditions, inflammation, allergies, pain, cardiovascular conditions, or skin conditions which comprises administering to a human in need of such treatment a pharmaceutically effective amount of a compound of claim
 1. 8. A pharmaceutical composition useful for inhibiting the biosynthesis of mammalian leukotrienes comprising a pharmaceutically acceptable carrier and an effective amount of a compound of claim
 1. 